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Signaling pathways from the endoplasmic reticulum and their roles in disease.

Kadowaki H, Nishitoh H - Genes (Basel) (2013)

Bottom Line: However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations.Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases.In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. kadowaki@med.miyazaki-u.ac.jp.

ABSTRACT
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

No MeSH data available.


Related in: MedlinePlus

Survival signaling under endoplasmic reticulum (ER) stress conditions. The accumulation of misfolded proteins activates three ER stress sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK). ATF6 is activated following cleavage with S1P and S2P, after transport to the Golgi. Activated ATF6 (ATF6(N)) functions as a transcription factor and induces the expression of ER chaperones and XBP1. Activated IRE1 induces the splicing of XBP1 messenger RNA (mRNA), and the resulting spliced XBP1 protein (XBP1s) translocates to the nucleus and controls the transcription of ER-resident chaperones and genes involved in lipogenesis and ER-associated degradation (ERAD). The activated PERK subsequently blocks general protein synthesis by phosphorylation of eIF2α, which enables the translation of eIF2α-activating transcription factor-4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control.
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genes-04-00306-f001: Survival signaling under endoplasmic reticulum (ER) stress conditions. The accumulation of misfolded proteins activates three ER stress sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK). ATF6 is activated following cleavage with S1P and S2P, after transport to the Golgi. Activated ATF6 (ATF6(N)) functions as a transcription factor and induces the expression of ER chaperones and XBP1. Activated IRE1 induces the splicing of XBP1 messenger RNA (mRNA), and the resulting spliced XBP1 protein (XBP1s) translocates to the nucleus and controls the transcription of ER-resident chaperones and genes involved in lipogenesis and ER-associated degradation (ERAD). The activated PERK subsequently blocks general protein synthesis by phosphorylation of eIF2α, which enables the translation of eIF2α-activating transcription factor-4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control.

Mentions: In mammals, the UPR signaling pathway is initiated by three ER membrane-associated sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK) (Figure 1). If the survival signal is insufficient to relieve the cells from ER stress, cells may undergo apoptosis to destroy ER stress-damaged cells. Many reports have shown that several molecules, including IRE1 [5,6], apoptosis signal-regulating kinase 1 (ASK1) [7], Bax/Bak [8,9,10], PERK, eIF2α-activating transcription factor-4 (ATF4) [11], and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP, also known as a growth arrest- and DNA damage-inducible gene 153 (GADD153)) [12,13], are related to ER stress-induced apoptosis signaling pathways (Figure 2). Dysfunction of the UPR, or prolonged ER stress, disrupts ER homeostasis. A large number of groups have described the relation between ER stress responses and a variety of human diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Therefore, it is important to understand the role of the UPR in the pathogenesis of these diseases. In this review, we summarize the molecular mechanisms of ER stress-induced survival and apoptosis signaling pathways and discuss the possibility that UPR signaling components could serve as potent therapeutic targets for the treatment of diseases.


Signaling pathways from the endoplasmic reticulum and their roles in disease.

Kadowaki H, Nishitoh H - Genes (Basel) (2013)

Survival signaling under endoplasmic reticulum (ER) stress conditions. The accumulation of misfolded proteins activates three ER stress sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK). ATF6 is activated following cleavage with S1P and S2P, after transport to the Golgi. Activated ATF6 (ATF6(N)) functions as a transcription factor and induces the expression of ER chaperones and XBP1. Activated IRE1 induces the splicing of XBP1 messenger RNA (mRNA), and the resulting spliced XBP1 protein (XBP1s) translocates to the nucleus and controls the transcription of ER-resident chaperones and genes involved in lipogenesis and ER-associated degradation (ERAD). The activated PERK subsequently blocks general protein synthesis by phosphorylation of eIF2α, which enables the translation of eIF2α-activating transcription factor-4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924831&req=5

genes-04-00306-f001: Survival signaling under endoplasmic reticulum (ER) stress conditions. The accumulation of misfolded proteins activates three ER stress sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK). ATF6 is activated following cleavage with S1P and S2P, after transport to the Golgi. Activated ATF6 (ATF6(N)) functions as a transcription factor and induces the expression of ER chaperones and XBP1. Activated IRE1 induces the splicing of XBP1 messenger RNA (mRNA), and the resulting spliced XBP1 protein (XBP1s) translocates to the nucleus and controls the transcription of ER-resident chaperones and genes involved in lipogenesis and ER-associated degradation (ERAD). The activated PERK subsequently blocks general protein synthesis by phosphorylation of eIF2α, which enables the translation of eIF2α-activating transcription factor-4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control.
Mentions: In mammals, the UPR signaling pathway is initiated by three ER membrane-associated sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK) (Figure 1). If the survival signal is insufficient to relieve the cells from ER stress, cells may undergo apoptosis to destroy ER stress-damaged cells. Many reports have shown that several molecules, including IRE1 [5,6], apoptosis signal-regulating kinase 1 (ASK1) [7], Bax/Bak [8,9,10], PERK, eIF2α-activating transcription factor-4 (ATF4) [11], and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP, also known as a growth arrest- and DNA damage-inducible gene 153 (GADD153)) [12,13], are related to ER stress-induced apoptosis signaling pathways (Figure 2). Dysfunction of the UPR, or prolonged ER stress, disrupts ER homeostasis. A large number of groups have described the relation between ER stress responses and a variety of human diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Therefore, it is important to understand the role of the UPR in the pathogenesis of these diseases. In this review, we summarize the molecular mechanisms of ER stress-induced survival and apoptosis signaling pathways and discuss the possibility that UPR signaling components could serve as potent therapeutic targets for the treatment of diseases.

Bottom Line: However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations.Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases.In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. kadowaki@med.miyazaki-u.ac.jp.

ABSTRACT
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

No MeSH data available.


Related in: MedlinePlus